The 8;21 translocation is one of the most common specific chromosomal rearrangements in acute myelogenous leukemia (AML). Our studies have led to the molecular cloning of the t(8;21) AML breakpoint and to the isolation of fusion transcripts. The chromosome 21 component of this fusion is derived from the AML1 gene, which we have found has striking similarity to the Drosophila segmentation gene, runt. The chromosome 8 gene, which we call ETO (for eight twenty-one), appears to be encoded over a large region of DNA (>0.5 megabase) with breakpoints occurring in a probable intron. We proposed to: 1) complete DNA sequence analysis of the fusion transcripts. In addition to the information gained regarding the potential functional significance of the fusion protein, we will use these data to develop PCR-based reagents for the sensitive detection of t(8;21) AML; 2) further characterize the AML1 and ETO genes. This will include the development of antibodies against the normal AML1 and ETO gene products for their use in immunocytochemical studies, as well as determination of the DNA sequence and chromosomal organization of the normal ETO gene, especially with regard to t(8;21) AML breakpoints; 3) investigate other leukemic translocation breakpoints involving 21q22.3, especially the 3;21 translocation associated with the blast crisis phase of CML and therapy-related myelodysplasia and acute leukemia.